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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Med.</journal-id>
<journal-title>Frontiers in Medicine</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Med.</abbrev-journal-title>
<issn pub-type="epub">2296-858X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fmed.2023.1211070</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Medicine</subject>
<subj-group>
<subject>Systematic Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Therapeutic prospect on umbilical cord mesenchymal stem cells in animal model with primary ovarian insufficiency: a meta-analysis</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name><surname>Wang</surname> <given-names>Xinrun</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="author-notes" rid="fn001"><sup>&#x02020;</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/2318059/overview"/>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name><surname>Li</surname> <given-names>Tianye</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="author-notes" rid="fn001"><sup>&#x02020;</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/2318301/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Bai</surname> <given-names>Xuechai</given-names></name>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/2318133/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Zhu</surname> <given-names>Yun</given-names></name>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/2319116/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Zhang</surname> <given-names>Meiliang</given-names></name>
<xref ref-type="aff" rid="aff4"><sup>4</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/1497690/overview"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Wang</surname> <given-names>Liang</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="corresp" rid="c001"><sup>&#x0002A;</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/2291336/overview"/>
</contrib>
</contrib-group>
<aff id="aff1"><sup>1</sup><institution>Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou</institution>, <addr-line>Zhejiang</addr-line>, <country>China</country></aff>
<aff id="aff2"><sup>2</sup><institution>Center for Reproductive Medicine, Department of Gynecology, Zhejiang Provincial People&#x00027;s Hospital (Affiliated People&#x00027;s Hospital, Hangzhou Medical College), Hangzhou</institution>, <addr-line>Zhejiang</addr-line>, <country>China</country></aff>
<aff id="aff3"><sup>3</sup><institution>Center for Clinical Big Data and Analytics, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou</institution>, <addr-line>Zhejiang</addr-line>, <country>China</country></aff>
<aff id="aff4"><sup>4</sup><institution>Department of Obstetrics and Gynecology, Yiwu Maternity and Children Hosptial, Yiwu Branch of Children&#x00027;s Hospital Zhejiang University School of Medicine, Yiwu</institution>, <addr-line>Zhejiang</addr-line>, <country>China</country></aff>
<author-notes>
<fn fn-type="edited-by"><p>Edited by: Yujiao Deng, The Second Affiliated Hospital of Xi&#x00027;an Jiaotong University, China</p></fn>
<fn fn-type="edited-by"><p>Reviewed by: Shengnan Yu, First Affiliated Hospital of Chongqing Medical University, China; Ping Li, Novo Nordisk, China; Xiaodi Huang, Peking Union Medical College Hospital (CAMS), China</p></fn>
<corresp id="c001">&#x0002A;Correspondence: Liang Wang <email>2196042&#x00040;zju.edu.cn</email></corresp>
<fn fn-type="equal" id="fn001"><p>&#x02020;These authors have contributed equally to this work</p></fn>
</author-notes>
<pub-date pub-type="epub">
<day>31</day>
<month>05</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="collection">
<year>2023</year>
</pub-date>
<volume>10</volume>
<elocation-id>1211070</elocation-id>
<history>
<date date-type="received">
<day>24</day>
<month>04</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>12</day>
<month>05</month>
<year>2023</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x000A9; 2023 Wang, Li, Bai, Zhu, Zhang and Wang.</copyright-statement>
<copyright-year>2023</copyright-year>
<copyright-holder>Wang, Li, Bai, Zhu, Zhang and Wang</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>Primary ovarian insufficiency (POI) leads to not only infertile but several adverse health events to women. Traditional treatment methods have their own set of limitations and drawbacks that vary in degree. Application of human umbilical cord mesenchymal stem cell (hUCMSC) is a promising strategy for POI. However, there is a lack of literatures on application of hUCMSC in human. Animal experimental model, however, can reflect the potential effectiveness of this employment. This study aimed to evaluate the curative effect of hUCMSC on animals with POI on a larger scale.</p>
</sec>
<sec>
<title>Methods</title>
<p>To gather data, Pubmed, Embase, and Cochrane Library were searched for studies published up to April 2022. Various indices, including the animals&#x00027; estrous cycle, serum sex hormone levels, and follicle number in the ovary, were compared between the experimental group and those with Premature Ovarian Insufficiency (POI).</p>
</sec>
<sec>
<title>Results</title>
<p>The administration of human umbilical cord-derived mesenchymal stem cells (hUCMSC) has been shown to significantly improve the estrous cycle (RR: 3.32, 95% CI: [1.80, 6.12], <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> = 0.0001), but robustly decrease its length (SMD: &#x02212;1.97, 95% CI: [&#x02212;2.58, &#x02212;1.36], <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> &#x0003C; 0.00001). It can also strikingly increase levels of serum estradiol (SMD: 5.34, 95% CI: [3.11, 7.57], <italic>I</italic><sup>2</sup> = 93%, <italic>P</italic> &#x0003C; 0.00001) and anti-m&#x000FC;llerian hormone (SMD: 1.92, 95% CI: [0.60, 3.25], <italic>I</italic><sup>2</sup> = 68%, <italic>P</italic> = 0.004). Besides, it lowers levels of serum follicle-stimulating hormone (SMD: &#x02212;3.02, 95% CI: [&#x02212;4.88, &#x02212;1.16], <italic>I</italic><sup>2</sup> = 93%, <italic>P</italic> = 0.001) and luteinising hormone (SMD: &#x02212;2.22, 95% CI: [&#x02212;3.67, &#x02212;0.76], <italic>I</italic><sup>2</sup> = 78%, <italic>P</italic> = 0.003), and thus collectively promotes folliculogenesis (SMD: 4.90, 95% CI: [3.92, 5.88], <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> &#x0003C; 0.00001).</p>
</sec>
<sec>
<title>Conclusions</title>
<p>Based on the presented findings, it is concluded that the administration of hUCMSC in animal models with POI can result in significant improvements in several key indicators, including estrous cycle recovery, hormone level modulation, and promotion of folliculogenesis. These positive outcomes suggest that hUCMSC may have potential as a treatment for POI in humans. However, further research is needed to establish the safety and efficacy of hUCMSC in humans before their clinical application.</p>
</sec>
<sec>
<title>Systematic review registration</title>
<p><ext-link ext-link-type="uri" xlink:href="https://inplasy.com/inplasy-2023-5-0075/">https://inplasy.com/inplasy-2023-5-0075/</ext-link>, identifier: INPLASY202350075.</p>
</sec>
</abstract>
<kwd-group>
<kwd>primary ovarian insufficiency</kwd>
<kwd>human umbilical cord mesenchymal stem cells</kwd>
<kwd>animal model</kwd>
<kwd>meta-analysis</kwd>
<kwd>estrous cycle</kwd>
<kwd>hormone level</kwd>
<kwd>folliculogenesis</kwd>
</kwd-group>
<counts>
<fig-count count="4"/>
<table-count count="4"/>
<equation-count count="0"/>
<ref-count count="61"/>
<page-count count="16"/>
<word-count count="9218"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Obstetrics and Gynecology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1. Introductions</title>
<p>Primary ovarian insufficiency (POI), also known as premature ovarian failure (POF), is a syndrome characterized by reduced or absent ovarian function (hypogonadism) and elevated levels of gonadotropins, specifically luteinising hormone (LH) and follicle-stimulating hormone (FSH) (hypergonadotropic) (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B2">2</xref>). This occurs due to the lack of negative sex-steroid and inhibin feedback. Therefore, POI is also referred to as hypergonadotropic hypogonadism. The condition is diagnosed when oocytes and the surrounding support cells are lost before the age of 40 years, along with serum FSH levels above the threshold range of 30&#x02013;40 mIU/mL twice (at least 1 month apart). POI is a systemic disease that can lead to various effects. Recent research has summarized the long-term health consequences of POI, including an increased risk of cardiovascular disease (CVD), decreased bone mineral density, significantly reduced fertility, psychological distress, vulvovaginal atrophy, neurological effects, and overall reduced life expectancy (<xref ref-type="bibr" rid="B3">3</xref>). While the incidence of POI is not peculiar, the underlying causes of this condition remain largely unknown (<xref ref-type="bibr" rid="B4">4</xref>). Despite extensive research, the etiology of POI is still not fully elucidated, and it is considered a complex and multifactorial condition. Genetic disorders, such as chromosomal abnormalities, are among the most prevalent causes of POI (<xref ref-type="bibr" rid="B5">5</xref>). These disorders can lead to early ovarian failure and an increased risk of POI. However, other factors like autoimmune diseases, iatrogenic injuries, and infectious diseases can also contribute to the onset of POI (<xref ref-type="bibr" rid="B6">6</xref>&#x02013;<xref ref-type="bibr" rid="B8">8</xref>). In some cases, autoimmune disorders like systemic lupus erythematosus or Hashimoto&#x00027;s thyroiditis can trigger the body&#x00027;s immune system to attack ovarian tissue, leading to POI (<xref ref-type="bibr" rid="B9">9</xref>). Additionally, with the increasement of gynaecologic cancer, medical treatments like chemotherapy, radiation therapy, or surgical removal of the ovaries can also cause damage to the ovarian tissue, leading to POI (<xref ref-type="bibr" rid="B10">10</xref>). Infections, such as mumps, tuberculosis, or sexually transmitted diseases like gonorrhea, can also contribute to POI by damaging the ovaries or disrupting their function (<xref ref-type="bibr" rid="B11">11</xref>). Given the complex and multifactorial nature of POI, early detection and timely intervention are crucial to help manage the condition and improve the quality of life of affected individuals. Therefore, a better understanding of the factors contributing to POI and advancements in diagnostic methods can aid in developing effective treatments and management strategies for this condition (<xref ref-type="bibr" rid="B12">12</xref>). Currently, traditional therapy for POI is limited. To patients without desire for pregnancy, hormone replacement therapy (HRT) is appropriate. HRT can significantly relieve POI symptoms and decrease bone fracture and CVD risks. It can even help fertility for those females who still have ovarian follicle reserve (<xref ref-type="bibr" rid="B13">13</xref>). Infertility treatment is another therapeutic aspect for POI. Oocyte donation is a traditional but useful way to help delivery, but is limited in many countries and regions. A way to preserve fertility is the cryopreservation of oocytes, embryos and ovarian tissues. For those who undergo radiotherapy, GnRH analog can help protect fertility, but some data are conflicting. Furthermore, a new method called <italic>in vitro</italic> activation (IVA) of dormant follicles can help patients with POI conceive as well (<xref ref-type="bibr" rid="B14">14</xref>). However, all of these therapies can be conducive to helping a small proportion of patients with POI. Human umbilical cord mesenchymal stem cell (hUCMSC) is mesenchymal stem cells derived from Wharton&#x00027;s jelly of a fetal umbilical cord. These cells have multiple differentiation potentials. They can generate cell types such as adipocytes, osteocytes and cartilage. In addition, neurons, astrocytes, glial cells, liver and islet cells are the potential lineage of hUCMSC (<xref ref-type="bibr" rid="B15">15</xref>). Stem cell therapy has been proposed for a long time. Some clinical trials have tried to understand the therapeutic effect of hUCMSC in POI. Evidence revealed follicular activated, estradiol (E<sub>2</sub>) increased and FSH decreased after hUCMSC transplantation in patients with POI (<xref ref-type="bibr" rid="B16">16</xref>, <xref ref-type="bibr" rid="B17">17</xref>). Collagen scaffold with hUCMSC is another stem cell delivery approach that has shown a therapeutic effect. In an <italic>in vivo</italic> study, hUCMSC activated primordial follicles by phosphorylating FOXO3a and FOXO1 (<xref ref-type="bibr" rid="B17">17</xref>). Apart from clinical trials, many studies tested the therapeutic effect of hUCMSC on the ovary of animals. For instance, hUCMSC introduction led to an atretic follicle decrease and a healthy antral follicle increase in mice. Granulosa cell (GC) apoptosis induced by POI was inhibited. Based on molecular analysis, the expression of SOD2, CAT and Bcl2 mRNA increased, whereas <italic>Bax</italic> mRNA expression declined (<xref ref-type="bibr" rid="B18">18</xref>). Given that these genes are associated with oxidation and apoptosis, hUCMSC infusion may influence the antioxidative and antiapoptotic procedures of the ovary. Furthermore, <italic>in vivo</italic> cell culture found that hUCMSC can secrete VEGF, IGF-1 and HGF (<xref ref-type="bibr" rid="B19">19</xref>). Through Sirius red and Masson trichrome staining of the ovary tissue, researchers found that fibrosis developed in POI rats, but after hUCMSC treatment, the fibrosis area was significantly reduced. The TGF-&#x003B2;<sub>1</sub> signaling pathway is a crucial immune regulative factors (<xref ref-type="bibr" rid="B20">20</xref>), also reportedly involved in hUCMSC regulation. The hUCMSC can inhibit the expression of TGF-&#x003B2;<sub>1</sub> and p-smad3 in the ovary, thereby depressing the differentiation of stromal cells into inner theca cells (TCs) and consequently inhibiting fibrosis in POI rats (<xref ref-type="bibr" rid="B21">21</xref>). However, only few integrated analyses have been found. Thus, this study aimed to summarize the results of animal studies investigating on hUCMSC and POI, form more valid evidence and confirm the therapeutic effect of hUCMSC on experimental animals compared with the POI model by analyzing the estrous cycle, serum sex hormone and ovarian follicles in the two groups.</p>
</sec>
<sec id="s2">
<title>2. Methods</title>
<p>This systematic meta-analysis appraises the association between employment of hUCMSC and the indices of ovarian reserve function in experimental animal models. We followed the preferred reporting items for meta-analysis and systematic review (PRISMA) 2020 guidelines and putting forward the research question using the PECOS format. We have registered at International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY). Registration number is INPLASY202350075.</p>
<sec>
<title>2.1. Search strategy</title>
<p>We searched the Pubmed, Embase and Cochrane Library databases. Specific search strategy is &#x0201C;((Primary Ovarian Insufficiency) OR (Premature Ovarian Failure) OR (Gonadotropin-Resistant Ovary Syndrome) OR (Hypergonadotropic Ovarian Failure)) AND ((Stem cell) OR (Progenitor Cell))&#x0201D;. To conclude, we used MeSH terms and their typical synonyms and combined them with &#x0201C;OR.&#x0201D; Then, we combined the results of &#x0201C;primary ovarian insufficiency&#x0201D; and &#x0201C;stem cell&#x0201D; with &#x0201C;AND.&#x0201D; All results from the date of database establishment to 1 April 2022 were included.</p>
</sec>
<sec>
<title>2.2. Inclusion and exclusion criteria</title>
<p>Initially, we excluded all duplicated studies. Subsequently, we collected studies that met the following criteria: female animals; hUCMSC; successful POF model establishment; and serum hormone, follicle count and estrous cycle as the outcome. Furthermore, the following five study types were excluded: reviews and meta-analysis, studies that are not associated with stem cell or POI, non-animal studies, case reports and animal studies without hUCMSC application. After selecting studies related to hUCMSC and POI, we thoroughly read the full text and further excluded studies that we failed to collect the exact data and studies with no outcomes that we aimed.</p>
</sec>
<sec>
<title>2.3. Data extraction and statistical analysis</title>
<p>Data were extracted and qualifiedly assessed by using &#x0201C;SYRCLE animal experiment bias risk assessment form.&#x0201D; We used risk ratios (RRs) with 95% confidence intervals (CI) for categorical data, and standardized mean difference (SMD) for numerical data to combine studies. If the heterogeneity test showed <italic>I</italic><sup>2</sup> &#x0003E; 50%, we used random effects model. Otherwise, we used fixed effects model. All statistical data were analyzed on RevMan 5.4 (<xref ref-type="bibr" rid="B22">22</xref>). The extracted data from each study included the first author, country or region, publishing year, experiment animal, POI model establishing method, hUCMSC intervention situation, group situation and outcome data. During the analysis, we firstly tested the heterogeneity of the studies and selected the effects model, as mentioned before. Then, we divided the studies according to unit, injection location, hUCMSC concentration, transplantation time and follicle type for the subgroup analyses. Sensitivity was assessed by eliminating studies one by one. We also used funnel plot to determine the publication bias. All statistical significances were defined at <italic>P</italic> &#x0003C; 0.05.</p>
</sec>
</sec>
<sec id="s3">
<title>3. Results</title>
<sec>
<title>3.1. Description of search results</title>
<p>We identified 446, 335 and 16 studies from Pubmed, Embase and Cochrane Library, respectively. Among them, 175 duplicate studies, 223 reviews or meta-analyses, 204 studies that are not associated with stem cell or POI, 26 animal studies, 44 case reports and 95 animal studies without hUCMSC used were excluded. Conclusively, 30 animal studies remained, and they were all correlated to hUCMSC and POI. After full text reading, we further excluded 16 studies because we failed to obtain the exact data, and three studies because they lack our aimed outcome. Ultimately, 11 studies were analyzed (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B23">23</xref>&#x02013;<xref ref-type="bibr" rid="B33">33</xref>).</p>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption><p>Flow diagram on search procedure of Pubmed, Embase and Cochrane Library and the exclusion criteria.</p></caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fmed-10-1211070-g0001.tif"/>
</fig>
</sec>
<sec>
<title>3.2. Basic characteristics and quality assessment</title>
<p>We extracted the data on the first author, country, publication year, experiment animal number and situation, model establishment situation, group situation, some outcomes and web link. We included nine studies from China (<xref ref-type="bibr" rid="B23">23</xref>, <xref ref-type="bibr" rid="B24">24</xref>, <xref ref-type="bibr" rid="B26">26</xref>, <xref ref-type="bibr" rid="B28">28</xref>&#x02013;<xref ref-type="bibr" rid="B33">33</xref>), one from Saudi Arabia (<xref ref-type="bibr" rid="B25">25</xref>) and one from Iran (<xref ref-type="bibr" rid="B27">27</xref>). A total of 158 stem cell&#x02013;treated animals and 155 POI model animals were included. Eight studies infused hUCMSC by tail vein (<xref ref-type="bibr" rid="B23">23</xref>, <xref ref-type="bibr" rid="B24">24</xref>, <xref ref-type="bibr" rid="B27">27</xref>&#x02013;<xref ref-type="bibr" rid="B31">31</xref>, <xref ref-type="bibr" rid="B33">33</xref>), whereas four injected hUCMSC directly into the ovary (<xref ref-type="bibr" rid="B25">25</xref>, <xref ref-type="bibr" rid="B26">26</xref>, <xref ref-type="bibr" rid="B29">29</xref>, <xref ref-type="bibr" rid="B32">32</xref>); in addition, one study compared the effects of these two methods (<xref ref-type="bibr" rid="B29">29</xref>). Stem cell concentrations varied, ranging from 1 &#x000D7; 10<sup>5</sup> to 5 &#x000D7; 10<sup>6</sup>. However, the concentration units in some studies were unclear; thus, we only conducted a subgroup analysis by stem cell concentration in hormone analyses. Transplantation time also varied. Some studies set a series of observation time to better show the effect of hUCMSC. To simplify our analysis, we only chose the data at the end of the study for our meta-analysis (<xref ref-type="table" rid="T1">Tables 1</xref>, <xref ref-type="table" rid="T2">2</xref>). In order to identify the effect of different transplantation time, we conducted a subgroup analysis as well.</p>
<table-wrap position="float" id="T1">
<label>Table 1</label>
<caption><p>Characteristics of the included studies.</p></caption> 
<table frame="box" rules="all">
<thead>
<tr style="background-color:&#x00023;919498;color:&#x00023;ffffff">
<th valign="top" align="left"><bold>First author</bold></th>
<th valign="top" align="left"><bold>Country</bold></th>
<th valign="top" align="left"><bold>Publication year</bold></th>
<th valign="top" align="left"><bold>Experiment animal</bold></th>
<th valign="top" align="left"><bold>Total animal numbers</bold></th>
<th valign="top" align="left"><bold>Animal age</bold></th>
<th valign="top" align="left"><bold>Model establishment</bold></th>
<th valign="top" align="left"><bold>Establishment time</bold></th>
<th valign="top" align="left"><bold>Transplantation time</bold></th>
<th valign="top" align="left"><bold>Transplantation route</bold></th>
<th valign="top" align="left"><bold>Available outcome<sup>&#x0002A;</sup></bold></th>
<th valign="top" align="left"><bold>Web link</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">Jian Shen</td>
<td valign="top" align="left">China</td>
<td valign="top" align="left">2020</td>
<td valign="top" align="left">BALB/c mice</td>
<td valign="top" align="left">110</td>
<td valign="top" align="left">7&#x02013;8 weeks old</td>
<td valign="top" align="left">Cyclophosphamide</td>
<td valign="top" align="left">14 d</td>
<td valign="top" align="left">60 d</td>
<td valign="top" align="left">tail vein</td>
<td valign="top" align="left">Estrous cycle; Follicle number; E<sub>2</sub>; FSH</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://www.wjgnet.com/1948-0210/full/v12/i4/277.htm">https://www.wjgnet.com/1948-0210/full/v12/i4/277.htm</ext-link></td>
</tr> <tr>
<td valign="top" align="left">He Jie</td>
<td valign="top" align="left">China</td>
<td valign="top" align="left">2021</td>
<td valign="top" align="left">BALB/C female mice</td>
<td valign="top" align="left">30</td>
<td valign="top" align="left">7 to 8 weeks</td>
<td valign="top" align="left">Cyclophosphamide &#x0002B; baixioan</td>
<td valign="top" align="left">1 d</td>
<td valign="top" align="left">15 d</td>
<td valign="top" align="left">tail vein</td>
<td valign="top" align="left">E<sub>2</sub>; FSH; AMH; LH; Follicle number</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://cellmolbiol.org/index.php/CMB/article/view/4071">https://cellmolbiol.org/index.php/CMB/article/view/4071</ext-link></td>
</tr> <tr>
<td valign="top" align="left">Amr K. Elfayomy</td>
<td valign="top" align="left">Saudi Arabia</td>
<td valign="top" align="left">2016</td>
<td valign="top" align="left">albino Wistar rats</td>
<td valign="top" align="left">95</td>
<td valign="top" align="left">-</td>
<td valign="top" align="left">Paclitaxel</td>
<td valign="top" align="left">1 d</td>
<td valign="top" align="left">6 wk</td>
<td valign="top" align="left"><italic>in situ</italic></td>
<td valign="top" align="left">Follicle number; E<sub>2</sub>; FSH</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://www.sciencedirect.com/science/article/pii/S0040816616300246?via%3Dihub">https://www.sciencedirect.com/science/article/pii/S0040816616300246?via%3Dihub</ext-link></td>
</tr> <tr>
<td valign="top" align="left">Xunyi Zhang</td>
<td valign="top" align="left">China</td>
<td valign="top" align="left">2020</td>
<td valign="top" align="left">SD rats</td>
<td valign="top" align="left">80</td>
<td valign="top" align="left">6&#x02013;8 weeks</td>
<td valign="top" align="left">pZP3 suspension</td>
<td valign="top" align="left">1 d</td>
<td valign="top" align="left">20 d</td>
<td valign="top" align="left"><italic>in situ</italic></td>
<td valign="top" align="left">Estrous cycle; E<sub>2</sub>; FSH; LH; Follicle number</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://www.tandfonline.com/doi/full/10.1080/09513590.2021.1878133">https://www.tandfonline.com/doi/full/10.1080/09513590.2021.1878133</ext-link></td>
</tr> <tr>
<td valign="top" align="left">Ladan Jalalie</td>
<td valign="top" align="left">Iran</td>
<td valign="top" align="left">2021</td>
<td valign="top" align="left">C57BL/6 mice</td>
<td valign="top" align="left">30</td>
<td valign="top" align="left">6&#x02013;8-week-old</td>
<td valign="top" align="left">Cyclophosphamide</td>
<td valign="top" align="left">15 d</td>
<td valign="top" align="left">1 wk</td>
<td valign="top" align="left">tail vein</td>
<td valign="top" align="left">Follicle number; FSH; E<sub>2</sub></td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://www.sciencedirect.com/science/article/abs/pii/S0065128120301574?via%3Dihub">https://www.sciencedirect.com/science/article/abs/pii/S0065128120301574?via%3Dihub</ext-link></td>
</tr> <tr>
<td valign="top" align="left">Taoran Deng</td>
<td valign="top" align="left">China</td>
<td valign="top" align="left">2021</td>
<td valign="top" align="left">C57BL/6 mice</td>
<td valign="top" align="left">27</td>
<td valign="top" align="left">6&#x02013;7 weeks old</td>
<td valign="top" align="left">Cyclophosphamide and busulfan</td>
<td valign="top" align="left">1 d</td>
<td valign="top" align="left">2 wk</td>
<td valign="top" align="left">tail vein</td>
<td valign="top" align="left">Estrous cycle; Follicle number; E<sub>2</sub>; FSH</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://link.springer.com/article/10.1007/s43032-021-00499-1">https://link.springer.com/article/10.1007/s43032-021-00499-1</ext-link></td>
</tr> <tr>
<td valign="top" align="left">Dan Song</td>
<td valign="top" align="left">China</td>
<td valign="top" align="left">2016</td>
<td valign="top" align="left">Wistar rats</td>
<td valign="top" align="left">40</td>
<td valign="top" align="left">8 weeks old</td>
<td valign="top" align="left">Cyclophosphamide</td>
<td valign="top" align="left">1 d</td>
<td valign="top" align="left">6 wk</td>
<td valign="top" align="left">tail vein&#x0002B;<italic>in situ</italic></td>
<td valign="top" align="left">E<sub>2</sub>; FSH; AMH; Follicle number</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://www.hindawi.com/journals/bmri/2016/2517514/">https://www.hindawi.com/journals/bmri/2016/2517514/</ext-link></td>
</tr> <tr>
<td valign="top" align="left">Zhe Wang</td>
<td valign="top" align="left">China</td>
<td valign="top" align="left">2020</td>
<td valign="top" align="left">SD rats</td>
<td valign="top" align="left">120</td>
<td valign="top" align="left">8 weeks old</td>
<td valign="top" align="left">Ovarian antigen</td>
<td valign="top" align="left">30 d</td>
<td valign="top" align="left">2 wk</td>
<td valign="top" align="left">tail vein</td>
<td valign="top" align="left">Estrous cycle; Follicle number</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://www.hindawi.com/journals/sci/2020/3249495/">https://www.hindawi.com/journals/sci/2020/3249495/</ext-link></td>
</tr>
<tr>
<td valign="top" align="left">Shufang Wang</td>
<td valign="top" align="left">China</td>
<td valign="top" align="left">2013</td>
<td valign="top" align="left">CD1 (ICR) mice</td>
<td valign="top" align="left">45</td>
<td valign="top" align="left">-</td>
<td valign="top" align="left">Cyclophosphamide</td>
<td valign="top" align="left">15 d</td>
<td valign="top" align="left">1 wk</td>
<td valign="top" align="left">tail vein</td>
<td valign="top" align="left">Follicle number</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://www.hindawi.com/journals/bmri/2013/690491/">https://www.hindawi.com/journals/bmri/2013/690491/</ext-link></td>
</tr> <tr>
<td valign="top" align="left">Yanjun Yang</td>
<td valign="top" align="left">China</td>
<td valign="top" align="left">2019</td>
<td valign="top" align="left">C57BL/6 mice</td>
<td valign="top" align="left">24</td>
<td valign="top" align="left">6 weeks old</td>
<td valign="top" align="left">Cyclophosphamide</td>
<td valign="top" align="left">15 d</td>
<td valign="top" align="left">4 wk</td>
<td valign="top" align="left"><italic>in situ</italic></td>
<td valign="top" align="left">Estrous cycle; E<sub>2</sub>; FSH; AMH; Follicle number</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://link.springer.com/article/10.1007/s11626-019-00337-4">https://link.springer.com/article/10.1007/s11626-019-00337-4</ext-link></td>
</tr>
<tr>
<td valign="top" align="left">Qun Zheng</td>
<td valign="top" align="left">China</td>
<td valign="top" align="left">2019</td>
<td valign="top" align="left">SD rats</td>
<td valign="top" align="left">40</td>
<td valign="top" align="left">12 weeks old</td>
<td valign="top" align="left">Cyclophosphamide</td>
<td valign="top" align="left">15 d</td>
<td valign="top" align="left">2 wk</td>
<td valign="top" align="left">tail vein</td>
<td valign="top" align="left">Estrous cycle; AMH; E<sub>2</sub>; FSH; Follicle number</td>
<td valign="top" align="left"><ext-link ext-link-type="uri" xlink:href="https://www.hindawi.com/journals/bmri/2019/6539294/">https://www.hindawi.com/journals/bmri/2019/6539294/</ext-link></td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p><sup>&#x0002A;</sup>Wang et al. (<xref ref-type="bibr" rid="B30">30</xref>), Wang et al. (<xref ref-type="bibr" rid="B31">31</xref>), and Zheng et al. (<xref ref-type="bibr" rid="B33">33</xref>) lack exact data of serum sex hormone.</p>
</table-wrap-foot>
</table-wrap>
<table-wrap position="float" id="T2">
<label>Table 2</label>
<caption><p>Quality assessment of the included studies.</p></caption> 
<table frame="box" rules="all">
<thead>
<tr style="background-color:&#x00023;919498;color:&#x00023;ffffff">
<th valign="top" align="left"><bold>Study</bold></th>
<th valign="top" align="left"><bold>&#x02460;</bold></th>
<th valign="top" align="left"><bold>&#x02461;</bold></th>
<th valign="top" align="left"><bold>&#x02462;</bold></th>
<th valign="top" align="left"><bold>&#x02463;</bold></th>
<th valign="top" align="left"><bold>&#x02464;</bold></th>
<th valign="top" align="left"><bold>&#x02465;</bold></th>
<th valign="top" align="left"><bold>&#x02466;</bold></th>
<th valign="top" align="left"><bold>&#x02467;</bold></th>
<th valign="top" align="left"><bold>&#x02468;</bold></th>
<th valign="top" align="left"><bold>&#x02469;</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="left">No</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr> <tr>
<td valign="top" align="left">Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr> <tr>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr> <tr>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr> <tr>
<td valign="top" align="left">Jalalie. et al. (<xref ref-type="bibr" rid="B27">27</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr> <tr>
<td valign="top" align="left">Deng. et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr> <tr>
<td valign="top" align="left">Song et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr> <tr>
<td valign="top" align="left">Wang et al. (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr> <tr>
<td valign="top" align="left">Wang et al. (<xref ref-type="bibr" rid="B30">30</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr> <tr>
<td valign="top" align="left">Yang et al. (<xref ref-type="bibr" rid="B31">31</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr>
<tr>
<td valign="top" align="left">Zheng et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Unknown</td>
<td valign="top" align="left">Yes</td>
<td valign="top" align="left">Yes</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>SYRCLE animal experiment bias risk assessment form: &#x02460; Distribution sequence production is sufficient &#x02461; Baselines of groups are the same &#x02462; Distribution concealing is sufficient &#x02463; Experiment animals are randomly fed &#x02464; Blinding to researcher &#x02465; Randomly select animals to assess result &#x02466; Blinding to result evaluator &#x02467; No incomplete data &#x02468; No selective result report &#x02469; No other biases.</p>
</table-wrap-foot>
</table-wrap>
</sec>
<sec>
<title>3.3. Analysis of outcomes</title>
<sec>
<title>3.3.1. Estrous cycle</title>
<p>Five studies reported estrous cycle situation (<xref ref-type="bibr" rid="B23">23</xref>, <xref ref-type="bibr" rid="B26">26</xref>, <xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B30">30</xref>, <xref ref-type="bibr" rid="B32">32</xref>). Two outcomes were used to divide them into two analyses. Of the five studies, two (<xref ref-type="bibr" rid="B23">23</xref>, <xref ref-type="bibr" rid="B30">30</xref>) calculated the proportion of animals with normal estrous cycle. Based on different cell concentrations, four groups were included in one analysis. The three other studies (<xref ref-type="bibr" rid="B26">26</xref>, <xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B32">32</xref>) measured the length of the estrous cycle in animals. Results showed that hUCMSC significantly improved the proportion of animals with normal estrous cycle (RR: 3.32, 95% CI: [1.80, 6.12], <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> = 0.0001; <xref ref-type="fig" rid="F2">Figure 2A</xref>) and shortened the estrous cycle length (SMD: &#x02212;1.97, 95% CI: [&#x02212;2.58, &#x02212;1.36], <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> &#x0003C; 0.00001; <xref ref-type="fig" rid="F2">Figure 2B</xref>). Based on the location of stem cell injection, the subgroup analysis showed that estrous cycle improvement is independent of the injection site (<xref ref-type="table" rid="T3">Table 3</xref>).</p>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption><p>Forest plot of animals&#x00027; estrous cycle situation in the hUCMSC group versus the POI model group. <bold>(A)</bold> Numerous animals in the hUCMSC group recovered normal estrous cycle compared with those in the POI model group (RR: 3.32, 95% CI: [1.80, 6.12], <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> = 0.0001). <bold>(B)</bold> The cycle length significantly decreased in the hUCMSC group compared with that in the POI model group (SMD: &#x02212;1.97, 95% CI: [&#x02212;2.58, &#x02212;1.36], <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> &#x0003C; 0.00001).</p></caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fmed-10-1211070-g0002.tif"/>
</fig>
<table-wrap position="float" id="T3">
<label>Table 3</label>
<caption><p>Subgroup analysis results of animals&#x00027; estrous cycle and serum hormone level.</p></caption> 
<table frame="box" rules="all">
<thead>
<tr style="background-color:&#x00023;919498;color:&#x00023;ffffff">
<th valign="top" align="left"><bold>Comparison</bold></th>
<th valign="top" align="center" colspan="6"><bold>Result</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left" rowspan="4">Estrous cycle length</td>
<td valign="top" align="left" style="background-color:#e6e6e6">Subgroup name</td>
<td valign="top" align="center" style="background-color:#e6e6e6">Study number</td>
<td valign="top" align="left" style="background-color:#e6e6e6">Included study</td>
<td valign="top" align="left" style="background-color:#e6e6e6">SMD [95%CI]</td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>I</italic><sup>2</sup></td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>P</italic></td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Injection location</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">Tail vein</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">&#x02212;1.58 [&#x02212;2.74, &#x02212;0.41]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.008</td>
</tr>
<tr>
<td valign="top" align="left"><italic>In situ</italic></td>
<td valign="top" align="center">2</td>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>); Yang et al. (<xref ref-type="bibr" rid="B34">34</xref>)</td>
<td valign="top" align="left">&#x02212;2.12 [&#x02212;2.83, &#x02212;1.41]</td>
<td valign="top" align="center">13%</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr> <tr>
<td valign="top" align="left" rowspan="19">E<sub>2</sub></td>
<td valign="top" align="left" style="background-color:#e6e6e6">Subgroup name</td>
<td valign="top" align="center" style="background-color:#e6e6e6">Study number</td>
<td valign="top" align="left" style="background-color:#e6e6e6">Included study</td>
<td valign="top" align="left" style="background-color:#e6e6e6">SMD [95%CI]</td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>I</italic><sup>2</sup></td>
<td valign="top" align="center" style="background-color:#e6e6e6">P</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Calculate unit</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">unknown</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="left">9.68 [4.09, 15.27]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.0007</td>
</tr>
<tr>
<td valign="top" align="left">pg/mL, ng/L</td>
<td valign="top" align="center">6</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Dan Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>); Jalalie et al. (<xref ref-type="bibr" rid="B27">27</xref>); Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="left">6.07 [2.84, 9.31]</td>
<td valign="top" align="center">94%</td>
<td valign="top" align="center">0.0002</td>
</tr>
<tr>
<td valign="top" align="left">ng/mL</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">0.25 [&#x02212;0.73, 1.24]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.62</td>
</tr>
<tr>
<td valign="top" align="left">pmol/L</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">6.41 [3.86, 8.95]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Injection location</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">Tail vein</td>
<td valign="top" align="center">5</td>
<td valign="top" align="left">Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>); Jalalie et al. (<xref ref-type="bibr" rid="B27">27</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>); Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">5.32 [1.86, 8.79]</td>
<td valign="top" align="center">92%</td>
<td valign="top" align="center">0.003</td>
</tr>
<tr>
<td valign="top" align="left"><italic>In situ</italic></td>
<td valign="top" align="center">4</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song&#x02013;<italic>in situ</italic> et al. (<xref ref-type="bibr" rid="B29">29</xref>); Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>); Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">6.25 [1.67, 10.82]</td>
<td valign="top" align="center">95%</td>
<td valign="top" align="center">0.007</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Stem cell concentration</bold></td>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">1 &#x000D7; 10E5</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="left">0.69 [0.05, 1.33]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.03</td>
</tr>
<tr>
<td valign="top" align="left">2 &#x000D7; 10E5</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">6.41 [3.86, 8.95]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left">1 &#x000D7; 10E6</td>
<td valign="top" align="center">5</td>
<td valign="top" align="left">Song&#x02013;tail vein et al. (<xref ref-type="bibr" rid="B29">29</xref>); Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>); Jalalie et al. (<xref ref-type="bibr" rid="B27">27</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>); Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">5.32 [1.86, 8.79]</td>
<td valign="top" align="center">92%</td>
<td valign="top" align="center">0.03</td>
</tr>
<tr>
<td valign="top" align="left">2 &#x000D7; 10E6</td>
<td valign="top" align="center">2</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="left">10.44 [&#x02212;6.37, 27.24]</td>
<td valign="top" align="center">97%</td>
<td valign="top" align="center">0.22</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Transplantation time</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">2 weeks or 15 days</td>
<td valign="top" align="center">5</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>); Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">2.26 [1.11, 3.42]</td>
<td valign="top" align="center">61%</td>
<td valign="top" align="center">0.0001</td>
</tr>
<tr>
<td valign="top" align="left">4 weeks or 30 days</td>
<td valign="top" align="center">5</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>); Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">3.91 [0.96, 6.86]</td>
<td valign="top" align="center">92%</td>
<td valign="top" align="center">0.009</td>
</tr>
<tr>
<td valign="top" align="left">6 weeks or 45 days</td>
<td valign="top" align="center">4</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="left">7.33 [1.87, 12.78]</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">0.008</td>
</tr>
<tr>
<td valign="top" align="left">60 days</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="left">9.68 [4.09, 15.27]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.0007</td>
</tr>
<tr>
<td valign="top" align="left" rowspan="12">AMH</td>
<td valign="top" align="center" style="background-color:#e6e6e6">Subgroup name</td>
<td valign="top" align="center" style="background-color:#e6e6e6">Study number</td>
<td valign="top" align="left" style="background-color:#e6e6e6">Included study</td>
<td valign="top" align="left" style="background-color:#e6e6e6">SMD [95%CI]</td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>I</italic><sup>2</sup></td>
<td valign="top" align="center" style="background-color:#e6e6e6">P</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Calculate unit</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">ng/mL</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="left">3.64 [2.11, 5.17]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left" style="background-color:#e6e6e6">Subgroup name</td>
<td valign="top" align="center" style="background-color:#e6e6e6">Study number</td>
<td valign="top" align="center" style="background-color:#e6e6e6">Included study</td>
<td valign="top" align="left" style="background-color:#e6e6e6">SMD [95%CI]</td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>I</italic><sup>2</sup></td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>P</italic></td>
</tr>
<tr>
<td valign="top" align="left">pg/mL</td>
<td valign="top" align="center">3</td>
<td valign="top" align="left">Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">1.14 [0.37, 1.92]</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">0.004</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Injection location</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">Tail vein</td>
<td valign="top" align="center">2</td>
<td valign="top" align="left">Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="left">2.84 [1.11, 4.57]</td>
<td valign="top" align="center">51%</td>
<td valign="top" align="center">0.001</td>
</tr>
<tr>
<td valign="top" align="left"><italic>In situ</italic></td>
<td valign="top" align="center">2</td>
<td valign="top" align="left">Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">1.00 [0.15, 1.85]</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">0.02</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Stem cell concentration</bold></td>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">2 &#x000D7; 10E5</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">0.81 [&#x02212;0.16, 1.78]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.1</td>
</tr>
<tr>
<td valign="top" align="left">1 &#x000D7; 10E6</td>
<td valign="top" align="center">2</td>
<td valign="top" align="left">Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="left">2.84 [1.11, 4.57]</td>
<td valign="top" align="center">51%</td>
<td valign="top" align="center">0.001</td>
</tr>
<tr>
<td valign="top" align="left">2 &#x000D7; 10E6</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="left">1.62 [&#x02212;0.16, 3.40]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.07</td>
</tr>
<tr>
<td valign="top" align="left" rowspan="19">FSH</td>
<td valign="top" align="left" style="background-color:#e6e6e6">Subgroup name</td>
<td valign="top" align="center" style="background-color:#e6e6e6">Study number</td>
<td valign="top" align="left" style="background-color:#e6e6e6">Included study</td>
<td valign="top" align="left" style="background-color:#e6e6e6">SMD [95%CI]</td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>I</italic><sup>2</sup></td>
<td valign="top" align="center" style="background-color:#e6e6e6">P</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Calculate unit</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">unknown</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="left">&#x02212;7.28 [&#x02212;11.56, &#x02212;3.00]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.0009</td>
</tr>
<tr>
<td valign="top" align="left">mIU/mL, U/L, IU/L</td>
<td valign="top" align="center">7</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>); Jalali et al. (<xref ref-type="bibr" rid="B27">27</xref>); Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>); Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">&#x02212;2.26 [&#x02212;4.11, &#x02212;0.41]</td>
<td valign="top" align="center">92%</td>
<td valign="top" align="center">0.02</td>
</tr>
<tr>
<td valign="top" align="left">pg/mL</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="left">&#x02212;5.27 [&#x02212;6.64, &#x02212;3.91]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Injection location</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">Tail vein</td>
<td valign="top" align="center">5</td>
<td valign="top" align="left">Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>); Jalali et al. (<xref ref-type="bibr" rid="B27">27</xref>); Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">&#x02212;2.51 [&#x02212;4.19, &#x02212;0.84]</td>
<td valign="top" align="center">82%</td>
<td valign="top" align="center">0.003</td>
</tr>
<tr>
<td valign="top" align="left"><italic>In situ</italic></td>
<td valign="top" align="center">4</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>); Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">&#x02212;3.40 [&#x02212;7.44, 0.65]</td>
<td valign="top" align="center">96%</td>
<td valign="top" align="center">0.1</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Stem cell concentration</bold></td>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">1 &#x000D7; 10E5</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="left">&#x02212;5.27 [&#x02212;6.64, &#x02212;3.91]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left">2 &#x000D7; 10E5</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="left">1.49 [0.41, 2.56]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.007</td>
</tr>
<tr>
<td valign="top" align="left">1 &#x000D7; 10E6</td>
<td valign="top" align="center">5</td>
<td valign="top" align="left">Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>); Jalali et al. (<xref ref-type="bibr" rid="B27">27</xref>); Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">&#x02212;2.51 [&#x02212;4.19, &#x02212;0.84]</td>
<td valign="top" align="center">82%</td>
<td valign="top" align="center">0.003</td>
</tr>
<tr>
<td valign="top" align="left">2 &#x000D7; 10E6</td>
<td valign="top" align="center">2</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="left">&#x02212;4.96 [&#x02212;11.50, 1.59]</td>
<td valign="top" align="center">95%</td>
<td valign="top" align="center">0.14</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Transplantation time</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">2 weeks or 15 days</td>
<td valign="top" align="center">5</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>); Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">&#x02212;2.10 [&#x02212;3.71, &#x02212;0.50]</td>
<td valign="top" align="center">79%</td>
<td valign="top" align="center">0.01</td>
</tr>
<tr>
<td valign="top" align="left">4 weeks or 30 days</td>
<td valign="top" align="center">5</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>); Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="left">&#x02212;3.28 [&#x02212;5.54, &#x02212;1.01]</td>
<td valign="top" align="center">86%</td>
<td valign="top" align="center">0.005</td>
</tr>
<tr>
<td valign="top" align="left" style="background-color:#e6e6e6">Subgroup name</td>
<td valign="top" align="left" style="background-color:#e6e6e6">Study number</td>
<td valign="top" align="center" style="background-color:#e6e6e6">Included study</td>
<td valign="top" align="left" style="background-color:#e6e6e6">SMD [95%CI]</td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>I</italic><sup>2</sup></td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>P</italic></td>
</tr>
<tr>
<td valign="top" align="left">6 weeks or 45 days</td>
<td valign="top" align="center">4</td>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>); Song et al.&#x02013;<italic>in situ</italic> (<xref ref-type="bibr" rid="B29">29</xref>); Song et al.&#x02013;tail vein (<xref ref-type="bibr" rid="B29">29</xref>); Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="center">&#x02212;4.03 [&#x02212;7.09, &#x02212;0.97]</td>
<td valign="top" align="center">87%</td>
<td valign="top" align="center">0.01</td>
</tr>
<tr>
<td valign="top" align="left">60 days</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="left">&#x02212;7.28 [&#x02212;11.56, &#x02212;3.00]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.0009</td>
</tr> <tr>
<td valign="top" align="left" rowspan="10">LH</td>
<td valign="top" align="left" style="background-color:#e6e6e6">Subgroup name</td>
<td valign="top" align="center" style="background-color:#e6e6e6">Study number</td>
<td valign="top" align="left" style="background-color:#e6e6e6">Included study</td>
<td valign="top" align="left" style="background-color:#e6e6e6">SMD [95%CI]</td>
<td valign="top" align="center" style="background-color:#e6e6e6"><italic>I</italic><sup>2</sup></td>
<td valign="top" align="center" style="background-color:#e6e6e6">P</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Calculate unit</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">mIU/mL</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="left">&#x02212;1.46 [&#x02212;2.47, &#x02212;0.45]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.005</td>
</tr>
<tr>
<td valign="top" align="left">pg/mL</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="left">&#x02212;2.94 [&#x02212;3.86, &#x02212;2.02]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Injection location</bold></td>
<td/>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">Tail vein</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="left">&#x02212;1.46 [&#x02212;2.47, &#x02212;0.45]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.005</td>
</tr>
<tr>
<td valign="top" align="left"><italic>In situ</italic></td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="left">&#x02212;2.94 [&#x02212;3.86, &#x02212;2.02]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left" colspan="2"><bold>Stem cell concentration</bold></td>
<td/>
<td/>
<td/>
</tr>
<tr>
<td valign="top" align="left">1 &#x000D7; 10E5</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="left">&#x02212;2.94 [&#x02212;3.86, &#x02212;2.02]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left">1 &#x000D7; 10E6</td>
<td valign="top" align="center">1</td>
<td valign="top" align="left">Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="left">&#x02212;1.46 [&#x02212;2.47, &#x02212;0.45]</td>
<td valign="top" align="center">Not applicable</td>
<td valign="top" align="center">0.005</td>
</tr></tbody>
</table>
</table-wrap>
</sec>
<sec>
<title>3.3.2. E<sub>2</sub></title>
<p>Eight studies reported serum E<sub>2</sub> levels (<xref ref-type="bibr" rid="B23">23</xref>&#x02013;<xref ref-type="bibr" rid="B29">29</xref>, <xref ref-type="bibr" rid="B32">32</xref>). Based on the injection location, nine groups were included in the analysis. Serum E<sub>2</sub> significantly increased in the hUCMSC group compared with that in the POI model group (SMD: 5.34, 95% CI: [3.11, 7.57], <italic>I</italic><sup>2</sup> = 93%, <italic>P</italic> &#x0003C; 0.00001; <xref ref-type="fig" rid="F3">Figure 3A</xref>). We conducted a subgroup analysis according to the statistical units, stem cell injection location and stem cell concentration. Besides, as some included studies compared several transplantation time, we also conducted a subgroup analysis based on it. The elevation of serum E<sub>2</sub> level was not significant when calculated by ng/mL or when the stem cell concentration was 2 &#x000D7; 10e6. However, the effect of hUCMSC on the serum E<sub>2</sub> level of animals was independent of the injection location. Significance was observed in all intervention time subgroup, indicating hUCMSC can increase serum E<sub>2</sub> level at the beginning of 2 weeks (<xref ref-type="table" rid="T3">Table 3</xref>).</p>
<fig id="F3" position="float">
<label>Figure 3</label>
<caption><p>Forest plot of animals&#x00027; serum hormone level and follicle number in the hUCMSC group vs. the POI model group. <bold>(A)</bold> Serum E<sub>2</sub> concentrations significantly increased in the hUCMSC group compared with those in the POI model group (SMD: 5.34, 95% CI: [3.11, 7.57], <italic>I</italic><sup>2</sup> = 93%, <italic>P</italic> &#x0003C; 0.00001). <bold>(B)</bold> Serum AMH concentrations significantly increased in the hUCMSC group compared with those in the POI model group (SMD: 1.92, 95% CI: [0.60, 3.25], <italic>I</italic><sup>2</sup> = 68%, <italic>P</italic> = 0.004). <bold>(C)</bold> Serum FSH concentrations significantly decreased in the hUCMSC group compared with those in the POI model group (SMD: &#x02212;3.02, 95% CI: [&#x02212;4.88, &#x02212;1.16], <italic>I</italic>2 = 93%, <italic>P</italic> = 0.001). <bold>(D)</bold> Serum LH concentrations significantly decreased in the hUCMSC group compared with those in the POI model group (SMD: &#x02212;2.22, 95% CI: [&#x02212;3.67, &#x02212;0.76], <italic>I</italic><sup>2</sup> = 78%, <italic>P</italic> = 0.003). <bold>(E)</bold> Ovarian follicle count comparison between the hUCMSC group versus the POI model group. Antral follicles (SMD: 4.64, 95% CI: [2.89, 6.39], <italic>I</italic><sup>2</sup> = 87%, <italic>P</italic> &#x0003C; 0.00001), pre-antral follicles (SMD: 1.73, 95% CI: [0.37, 3.10], <italic>I</italic><sup>2</sup> = 70%, <italic>P</italic> = 0.01), secondary follicles (SMD: 2.14, 95% CI: [1.07, 3.21], <italic>I</italic><sup>2</sup> = 84%, <italic>P</italic> &#x0003C; 0.0001), primary follicle (SMD: 2.23, 95% CI: [1.10, 3.35], <italic>I</italic><sup>2</sup> = 85%, <italic>P</italic> = 0.0001), primordial follicle (SMD: 1.68, 95% CI: [0.26, 3.09], <italic>I</italic><sup>2</sup> = 89%, <italic>P</italic> = 0.02) and all follicles (SMD: 4.90, 95% CI: [3.92, 5.88], <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> &#x0003C; 0.00001) increased significantly in the hUCMSC group compared with those in the POI model group.</p></caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fmed-10-1211070-g0003.tif"/>
</fig>
</sec>
<sec>
<title>3.3.3. AMH</title>
<p>Three studies reported serum AMH (<xref ref-type="bibr" rid="B24">24</xref>, <xref ref-type="bibr" rid="B29">29</xref>, <xref ref-type="bibr" rid="B32">32</xref>). Based on the injection location, four groups were included in the analysis. Serum AMH significantly increased in the hUCMSC group compared with that in the POI model group (SMD: 1.92, 95% CI: [0.60, 3.25], <italic>I</italic><sup>2</sup> = 68%, <italic>P</italic> = 0.004; <xref ref-type="fig" rid="F3">Figure 3B</xref>). The subgroup analysis revealed that serum AMH was independent of the statistical units and injection location. However, when the stem cell concentration was 2 &#x000D7; 10e5 and 2 &#x000D7; 10e6, no significant change was observed between the model and hUCMSC groups (<xref ref-type="table" rid="T3">Table 3</xref>).</p>
</sec>
<sec>
<title>3.3.4. FSH</title>
<p>Eight studies reported serum FSH levels (<xref ref-type="bibr" rid="B23">23</xref>&#x02013;<xref ref-type="bibr" rid="B29">29</xref>, <xref ref-type="bibr" rid="B32">32</xref>). Based on the injection location, nine groups were included in the analysis. Compared with the POI model group, the hUCMSC group showed a significant reduction in serum FSH (SMD: &#x02212;3.02, 95% CI: [&#x02212;4.88, &#x02212;1.16], <italic>I</italic><sup>2</sup> = 93%, <italic>P</italic> = 0.001; <xref ref-type="fig" rid="F3">Figure 3C</xref>). According to the statistical units, stem cell injection location, stem cell concentration and transplantation time, the subgroup analysis showed that no significant change was observed when hUCMSC was injected <italic>in situ</italic> and when the stem cell concentration was 2 &#x000D7; 10e6. However, in most cases, the FSH level decreased significantly after hUCMSC injection. Meanwhile, FSH decreases significantly 2 weeks after hUCMSC injection, indicating the effect of hUCMSC works at the beginning of 2 weeks (<xref ref-type="table" rid="T3">Table 3</xref>).</p>
</sec>
<sec>
<title>3.3.5. LH</title>
<p>Two studies reported serum LH (<xref ref-type="bibr" rid="B24">24</xref>, <xref ref-type="bibr" rid="B26">26</xref>). Given that they used different calculation units, injection location and stem cell concentration, we conducted a subgroup analysis. Compared with the POI model group, the hUCMSC group showed a significant decrease in serum LH (SMD: &#x02212;2.22, 95% CI: [&#x02212;3.67, &#x02212;0.76], <italic>I</italic><sup>2</sup> = 78%, <italic>P</italic> = 0.003; <xref ref-type="fig" rid="F3">Figure 3D</xref>). Subgroup analysis results showed that the treatment effect on LH concentration was independent of the calculation unit, injection location and stem cell concentration (<xref ref-type="table" rid="T3">Table 3</xref>).</p>
</sec>
<sec>
<title>3.3.6. Follicle number</title>
<p>Ten studies determined the follicle count in animals (<xref ref-type="bibr" rid="B24">24</xref>&#x02013;<xref ref-type="bibr" rid="B33">33</xref>). However, considering the various follicle types, we only conducted a subgroup analysis based on the follicle types (<xref ref-type="fig" rid="F3">Figure 3E</xref>). All subgroups, except the atresia follicles (<italic>P</italic> = 0.08) and corpus luteum (<italic>P</italic> = 0.45), showed significant differences. After hUCMSC injection, the antral follicles (SMD: 4.64, 95% CI: [2.89, 6.39], <italic>I</italic><sup>2</sup> = 87%, <italic>P</italic> &#x0003C; 0.00001), secondary follicles (SMD: 2.14, 95% CI: [1.07, 3.21], <italic>I</italic><sup>2</sup> = 84%, <italic>P</italic> &#x0003C; 0.0001), primordial follicles (SMD: 1.68, 95% CI: [0.26, 3.09], <italic>I</italic><sup>2</sup> = 89%, <italic>P</italic> = 0.02), pre-antral follicles (SMD: 1.73, 95% CI: [0.37, 3.10], <italic>I</italic><sup>2</sup> = 70%, <italic>P</italic> = 0.01), primary follicles (SMD: 2.23, 95% CI: [1.10, 3.35], <italic>I</italic><sup>2</sup> = 85%, <italic>P</italic> = 0.0001) and all follicles (SMD: 4.90, 95% CI: [3.92, 5.88], <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> &#x0003C; 0.00001) significantly increased compared with those in the POI model group.</p>
</sec>
</sec>
<sec>
<title>3.4. Sensitivity analysis</title>
<p>By picking out studies one by one, we conducted a sensitivity analysis on five outcomes of the estrous cycle, E<sub>2</sub>, FSH, AMH and LH. Results of the estrous cycle, E<sub>2</sub>, FSH and LH were stable, but after picking out Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>) or Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>), the heterogeneity of the AMH outcome reduced significantly (Jie et al.: <italic>I</italic><sup>2</sup> = 0%, <italic>P</italic> = 0.53; Yang et al.: <italic>I</italic><sup>2</sup> = 43%, <italic>P</italic> = 0.17). The data unit, transplantation time and study animals may explain the heterogeneity; larger data are needed to determine the origin (<xref ref-type="table" rid="T4">Table 4</xref>).</p>
<table-wrap position="float" id="T4">
<label>Table 4</label>
<caption><p>Sensitivity analysis of the results.</p></caption> 
<table frame="box" rules="all">
<thead>
<tr style="background-color:&#x00023;919498;color:&#x00023;ffffff">
<th valign="top" align="left"><bold>Outcome</bold></th>
<th valign="top" align="left"><bold>Excluded study</bold></th>
<th valign="top" align="center"><bold>Number of observation</bold></th>
<th valign="top" align="center"><italic><bold>I</bold></italic><bold><sup>2</sup></bold></th>
<th valign="top" align="center"><bold>SMD/RR [95%CI]</bold></th>
<th valign="top" align="center"><bold>P value of overall effect</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left" rowspan="5">Normal estrous cycle proportion</td>
<td valign="top" align="left">&#x02013;</td>
<td valign="top" align="center">4</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">3.32 [1.80, 6.12]</td>
<td valign="top" align="center">0.0001</td>
</tr>
<tr>
<td valign="top" align="left">Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="left">3</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">3.11 [1.66, 5.82]</td>
<td valign="top" align="center">0.0004</td>
</tr>
<tr>
<td valign="top" align="left">Wang&#x02013;High et al. (<xref ref-type="bibr" rid="B30">30</xref>)</td>
<td valign="top" align="center">3</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">2.85 [1.32, 6.13]</td>
<td valign="top" align="center">0.008</td>
</tr>
<tr>
<td valign="top" align="left">Wang&#x02013;Low et al. (<xref ref-type="bibr" rid="B30">30</xref>)</td>
<td valign="top" align="center">3</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">4.08 [1.99, 8.37]</td>
<td valign="top" align="center">0.0001</td>
</tr>
<tr>
<td valign="top" align="left">Wang&#x02013;Medium et al. (<xref ref-type="bibr" rid="B30">30</xref>)</td>
<td valign="top" align="center">3</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">3.31 [1.57, 6.97]</td>
<td valign="top" align="center">0.002</td>
</tr> <tr>
<td valign="top" align="left" rowspan="4">Duration of estrous cycle</td>
<td valign="top" align="left">&#x02013;</td>
<td valign="top" align="center">3</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">&#x02212;1.97 [&#x02212;2.58, &#x02212;1.36]</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B18">18</xref>)</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">43%</td>
<td valign="top" align="center">&#x02212;1.99 [&#x02212;2.98, &#x02212;1.00]</td>
<td valign="top" align="center">&#x0003C; 0.0001</td>
</tr>
<tr>
<td valign="top" align="left">Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">&#x02212;1.84 [&#x02212;2.48, &#x02212;1.20]</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left">Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">13%</td>
<td valign="top" align="center">&#x02212;2.12 [&#x02212;2.83, &#x02212;1.41]</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr> <tr>
<td valign="top" align="left" rowspan="10">E<sub>2</sub></td>
<td valign="top" align="center">&#x02013;</td>
<td valign="top" align="center">9</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">5.34 [3.11, 7.57]</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left">Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">4.95 [2.69, 7.20]</td>
<td valign="top" align="center">&#x0003C; 0.0001</td>
</tr>
<tr>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">90%</td>
<td valign="top" align="center">3.89 [2.00, 5.79]</td>
<td valign="top" align="center">&#x0003C; 0.0001</td>
</tr>
<tr>
<td valign="top" align="left">Song&#x02013;<italic>in situ</italic> et al. (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">94%</td>
<td valign="top" align="center">5.93 [3.42, 8.44]</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left">Song&#x02013;tail vein et al. (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">94%</td>
<td valign="top" align="center">5.96 [3.44, 8.48]</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left">Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">5.47 [3.06, 7.89]</td>
<td valign="top" align="center">&#x0003C; 0.00001</td>
</tr>
<tr>
<td valign="top" align="left">Jalalie et al. (<xref ref-type="bibr" rid="B27">27</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">92%</td>
<td valign="top" align="center">4.35 [2.26, 6.44]</td>
<td valign="top" align="center">&#x0003C; 0.0001</td>
</tr>
<tr>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">6.51 [3.48, 9.54]</td>
<td valign="top" align="center">&#x0003C; 0.0001</td>
</tr>
<tr>
<td valign="top" align="left">Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">6.49 [3.60, 9.38]</td>
<td valign="top" align="center">&#x0003C; 0.0001</td>
</tr>
<tr>
<td valign="top" align="left">Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">5.13 [2.83, 7.43]</td>
<td valign="top" align="center">&#x0003C; 0.0001</td>
</tr> <tr>
<td valign="top" align="left" rowspan="10">FSH</td>
<td valign="top" align="left">&#x02013;</td>
<td valign="top" align="center">9</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">&#x02212;3.02 [&#x02212;4.88, &#x02212;1.16]</td>
<td valign="top" align="center">0.001</td>
</tr>
<tr>
<td valign="top" align="left">Shen et al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">&#x02212;2.67 [&#x02212;4.57, &#x02212;0.77]</td>
<td valign="top" align="center">0.006</td>
</tr>
<tr>
<td valign="top" align="left">Elfayomy et al. (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">91%</td>
<td valign="top" align="center">&#x02212;2.35 [&#x02212;4.09, &#x02212;0.62]</td>
<td valign="top" align="center">0.008</td>
</tr>
<tr>
<td valign="top" align="left">Song&#x02013;<italic>in situ</italic> et al. (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">94%</td>
<td valign="top" align="center">&#x02212;3.22 [&#x02212;5.29, &#x02212;1.15]</td>
<td valign="top" align="center">0.002</td>
</tr>
<tr>
<td valign="top" align="left">Song&#x02013;tail vein et al. (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">94%</td>
<td valign="top" align="center">&#x02212;3.21 [&#x02212;5.27, &#x02212;1.15]</td>
<td valign="top" align="center">0.002</td>
</tr>
<tr>
<td valign="top" align="left">Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">94%</td>
<td valign="top" align="center">&#x02212;3.35 [&#x02212;5.61, &#x02212;1.09]</td>
<td valign="top" align="center">0.004</td>
</tr>
<tr>
<td valign="top" align="left">Jalalie et al. (<xref ref-type="bibr" rid="B27">27</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">&#x02212;2.76 [&#x02212;4.71, &#x02212;0.82]</td>
<td valign="top" align="center">0.005</td>
</tr>
<tr>
<td valign="top" align="left">Deng et al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">93%</td>
<td valign="top" align="center">&#x02212;3.39 [&#x02212;5.60, &#x02212;1.18]</td>
<td valign="top" align="center">0.003</td>
</tr>
<tr>
<td valign="top" align="left">Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">90%</td>
<td valign="top" align="center">&#x02212;3.60 [&#x02212;5.39, &#x02212;1.81]</td>
<td valign="top" align="center">&#x0003C; 0.0001</td>
</tr>
<tr>
<td valign="top" align="left">Zhang et al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="top" align="center">8</td>
<td valign="top" align="center">91%</td>
<td valign="top" align="center">&#x02212;2.68 [&#x02212;4.51, &#x02212;0.84]</td>
<td valign="top" align="center">0.004</td>
</tr> <tr>
<td valign="top" align="left" rowspan="5">AMH</td>
<td valign="top" align="center">&#x02013;</td>
<td valign="top" align="center">4</td>
<td valign="top" align="center">68%</td>
<td valign="top" align="center">1.92 [0.60, 3.25]</td>
<td valign="top" align="center">0.004</td>
</tr>
<tr>
<td valign="top" align="left">Jie et al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="center">3</td>
<td valign="top" align="center">0%</td>
<td valign="top" align="center">1.14 [0.37, 1.92]</td>
<td valign="top" align="center">0.004</td>
</tr>
<tr>
<td valign="top" align="left">Song&#x02013;<italic>in situ</italic> et al. (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="center">3</td>
<td valign="top" align="center">79%</td>
<td valign="top" align="center">2.04 [0.25, 3.84]</td>
<td valign="top" align="center">0.03</td>
</tr>
<tr>
<td valign="top" align="left">Song&#x02013;tail vein et al. (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="top" align="center">3</td>
<td valign="top" align="center">79%</td>
<td valign="top" align="center">1.97 [0.21, 3.72]</td>
<td valign="top" align="center">0.03</td>
</tr>
<tr>
<td valign="top" align="left">Yang et al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="top" align="center">3</td>
<td valign="top" align="center">43%</td>
<td valign="top" align="center">2.46 [1.14, 3.78]</td>
<td valign="top" align="center">0.0003</td>
</tr></tbody>
</table>
</table-wrap>
</sec>
<sec>
<title>3.5. Publication bias</title>
<p>Funnel plots of the normal estrous cycle proportion, E<sub>2</sub>, FSH and follicle number are asymmetric, whereas those of the estrous cycle length, AMH and LH are symmetric. Publication bias likely existed, especially in the results of the estrous cycle, E<sub>2</sub>, FSH and follicle number (<xref ref-type="fig" rid="F4">Figure 4</xref>).</p>
<fig id="F4" position="float">
<label>Figure 4</label>
<caption><p>Funnel plots of the <bold>(A)</bold> normal estrous cycle, <bold>(B)</bold> estrous cycle length, <bold>(C)</bold> serum E<sub>2</sub>, <bold>(D)</bold> serum FSH, <bold>(E)</bold> serum AMH, <bold>(F)</bold> serum LH and <bold>(G)</bold> follicle count.</p></caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fmed-10-1211070-g0004.tif"/>
</fig>
</sec>
</sec>
<sec id="s4">
<title>4. Discussions</title>
<p>In the year 1942, POI was initially described as a mysterious ailment that perplexed medical practitioners. As the medical community&#x00027;s focus began to shift toward unraveling its elusive nature, POI gradually gained notoriety and its prevalence surged to an alarming 1% (<xref ref-type="bibr" rid="B35">35</xref>). Chemical injury is a common method to establish POI model and a main cause of POI clinically apart from genetic disorders (<xref ref-type="bibr" rid="B12">12</xref>, <xref ref-type="bibr" rid="B36">36</xref>). But the pathophysiological change of POI is similar regardless of etiology. According to our results, the reduced ovarian function and elevated gonadotropins is reversed by hUCMSC therapy. Follicles are stimulated as well. Therefore, we think the therapeutic effect of hUCMSC is adaptable to all causes. The traditional treatment for POI is HRT, but it only relieves symptoms. The ovarian function remains poor and bring many clinical adverse events about in many patients. In a retrospective cohort study, only 3 of 20 patients achieved pregnancy by assisted reproductive technology (ART) (<xref ref-type="bibr" rid="B37">37</xref>). Besides, patients with HRT are more likely to develop sleep problems (<xref ref-type="bibr" rid="B38">38</xref>). Given these limitations, stem cell therapy has gained considerable attention recently. Currently, hUCMSC has two other different forms to apply, that is, the microvesicles (<xref ref-type="bibr" rid="B34">34</xref>) and extracellular vesicles (<xref ref-type="bibr" rid="B39">39</xref>) derived from such cells. Stem cells in the umbilical cord are easy to acquire and do not cause extra donor injury compared with the other stem cell types. Considering their proliferative ability, multidifferentiation and safety, hUCMSC has been researched in the treatment of respiratory (<xref ref-type="bibr" rid="B40">40</xref>), cardiovascular (<xref ref-type="bibr" rid="B41">41</xref>), liver (<xref ref-type="bibr" rid="B42">42</xref>), central nervous system (<xref ref-type="bibr" rid="B43">43</xref>, <xref ref-type="bibr" rid="B44">44</xref>) and autoimmune (<xref ref-type="bibr" rid="B45">45</xref>) diseases as well as diabetes (<xref ref-type="bibr" rid="B46">46</xref>). AMH is crucial in POI diagnosis. In our search on POI, AMH research has gained a large proportion. Physiologically, AMH is secreted by primary ovarian follicles and can negatively regulate the progression of earlier resting follicles into active and progressive ones (<xref ref-type="bibr" rid="B47">47</xref>). Considering that AMH secretion slightly varies in menstrual cycle and only healthy follicles secrete it, AMH is considered as a stable marker of ovarian reserve and POI. Our results showed a significant increase of AMH in the hUCMSC group, possibly because of the cytokine secreted by hUCMSC. However, the follicle number increased after stem cell transplantation; the proliferation of healthy follicles may be the cause of the AMH increase. Further research is needed to elucidate the underlying mechanism.</p>
<p>Many factors contribute to the development of infertility. And the gene expressions of different cases are various according to the diseases as a bioinformatic analysis showed (<xref ref-type="bibr" rid="B48">48</xref>). As a result, there are only some general treatments of infertility like IVF-ET and artificial insemination. Etiology based therapy of infertility is rare. Infertility therapies are mainly ART, aiming at gaining embryo directly (<xref ref-type="bibr" rid="B49">49</xref>). Our meta-analysis confirms folliculogenesis of hUCMSC in animal models, providing an etiology-specific therapy of POI. Apart from efficacy, safety is another important factors under evaluation. Although our result does not cover safety concerns, several phase 1/2 trials have been conducted for hUCMSC in other diseases. General outcomes for safety consideration include immediate infusion related adverse events, blood test like hepatic and renal function and blood cell count, inflammatory cytokine level, hypersensitive, infection, tumorigenesis (<xref ref-type="bibr" rid="B50">50</xref>&#x02013;<xref ref-type="bibr" rid="B52">52</xref>). No adverse event is observed in these studies.</p>
<p>Although many studies tried to determine the mechanism of hUCMSC, the specific target remains unclear. Apoptosis regulation was often observed in many animal studies. This result may be derived from some signaling pathways. In a previous study, the expression of CK 8/18, TGF-&#x000DF; and PCNA increased, while that of CASP-3 decreased (<xref ref-type="bibr" rid="B25">25</xref>). Other candidate molecular signals include Bcl-2 (<xref ref-type="bibr" rid="B53">53</xref>) and PI3K-Akt (<xref ref-type="bibr" rid="B54">54</xref>). Some researchers also hypothesized that angiogenesis can explain the anti-apopotic effect of hUCMSC (<xref ref-type="bibr" rid="B32">32</xref>). Further studies should be conducted to determine the exact mechanism and guide the clinical application of hUCMSC. However, hUCMSC can definitely promote ovarian function. Not only AMH but also E<sub>2</sub>, FSH and LH showed significant changes. Estrogen is mainly produced in the ovarian follicle, and LH and FSH play a crucial role. In addition, GCs and their aromatase convert androgen into estrogen (<xref ref-type="bibr" rid="B55">55</xref>). Our results proved the therapeutic effect of hUCMSC on E<sub>2</sub>, FSH and LH. We also found some pioneering clinical trials, and their results are optimistic. They investigate antral follicle number and sex hormone of patients to evaluate their ovary function. After UCMSC transplantation, patients showed significant recovery of sex hormone, with decreased level of FSH and increased number of antral follicle (<xref ref-type="bibr" rid="B16">16</xref>, <xref ref-type="bibr" rid="B17">17</xref>). Further pregnancy follow up showed that UCMSC transplantation does not affect genetic source of fetus (<xref ref-type="bibr" rid="B16">16</xref>). Ovarian volume increases after hUCMSC transplantation with significance, but no significance was observed in collagen scaffold group (<xref ref-type="bibr" rid="B17">17</xref>). Nevertheless, compared with animal studies, number of high-quality randomized controlled trials (RCTs) is little. Considering the differences between animals and humans, our meta-analysis result cannot fully support stem cell therapy in POI in human, but can provide a preclinical evidence. However, given that hUCMSC is proven to be effective in POI animals, researchers may pay more attention to RCTs. With abundant and valid RCT evidence, further application of stem cells can be discussed in the future. According to quality assessment table (<xref ref-type="table" rid="T2">Table 2</xref>), major problems are insufficient randomization and blinding. Thus, it is necessary for researchers to exactly illustrate their randomization settings and blinding measures to prove the function of hUCMSC especially in clinical stage. Traditionally, ovarian follicle number is thought to be fixed and decreases by age (<xref ref-type="bibr" rid="B56">56</xref>). So folliculogenesis is traditionally thought as an irreversible procedure. Besides, traditional therapy such as HRT can only relieve symptoms. Fertility preservation is indeed hard to achieve. But recently, the discovery of stem cell in ovary gives a new hope for ovarian regeneration. Germline stem cell (GSC) is identified and isolated from human ovarian cortex. The property of isolated stem cell is proved to be stable after cell culture. <italic>DDX4, OCT4. IFITM3</italic> and <italic>BLIMP-1</italic> are confirmed to be expressed by the GSC (<xref ref-type="bibr" rid="B57">57</xref>). Moreover, it can promote ovarian function recovery in sterile animals and achieve pregnancy (<xref ref-type="bibr" rid="B58">58</xref>). As our result shows a recovery of ovarian follicle after hUCMSC transplantation. Given the genetic origin of offspring is not from hUCMSC donor as clinical trial proves (<xref ref-type="bibr" rid="B16">16</xref>), new experiments can pay some attentions to the effect of hUCMSC on ovarian GSC to explore the mechanism. Many genes can regulate folliculogenesis. Genes, cells or molecules such as <italic>SP1, mTOR, Ube2i, YAP1, C1QTNF3, GPR173</italic>, ovarian fat pad factors, &#x003B1;<italic>-SNAP</italic>, CD11c<sup>&#x0002B;</sup> cells, M1 M&#x003A6;s and DCs all play a role in folliculogenesis (<xref ref-type="bibr" rid="B59">59</xref>). Some studies have tried to find the association between these genes and the hUCMSC treatment effect. For example, Lu Xueyan et al. found that hUCMSC can inhibit the autophagy of theca-interstitial cells via the AMPK/mTOR signaling pathway (<xref ref-type="bibr" rid="B60">60</xref>). Depending on our results, folliculogenesis is a promising direction. Considering that folliculogenesis is tightly connected to anti-apoptosis in GCs (<xref ref-type="bibr" rid="B61">61</xref>), some cytokines that can affect GCs may be the target of future mechanism research.</p>
<p>Finally, this study has some limitations that should not be ignored. Clinical study of hUCMSC is rare, and this is also one reason for us to conduct this meta-analysis. Preclinical study is an important part of scientific experiment. Because of limited number of clinical data, it is not the optimal time to conduct a clinical meta-analysis. The meta-analysis of preclinical animal study can promote the development of clinical trails. The relatively insufficient included study, medium quality, high diversity and heterogeneity restrict the application of conclusion. Though random effects model was applied in the analysis, the impact cannot be fully eliminated. All included studies are of medium-quality studies, and higher-quality studies are needed in future research. Due to the limited number of studies, publication bias likely exists in this meta-analysis. However, according to current results, hUCMSC is able to recover ovarian function of POI animals. The result is not affected by limitation. The mentioned limitation should be considered when our conclusion serves as an evidence for clinical study. Thus, we hold a conservative but optimistic view and think more studies are needed in the future to further support the results. Considering the characteristic table, we can observe that a standard animal study procedure has not been formed yet. Future research may focus on a suitable stem cell concentration and transplantation time to eliminate heterogeneity.</p>
</sec>
<sec id="s5">
<title>5. Conclusions</title>
<p>The transplantation of hUCMSC has the potential to restore the estrous cycle, increase E<sub>2</sub> and AMH levels, decrease FSH and LH levels, and promote folliculogenesis in female rodent models. The results strongly support the use of this therapeutic strategy with a promising outlook. It is important to evaluate the safety and effectiveness of hUCMSC in clinical trials. Randomized controlled trials should also be approached with caution, and safety and adverse effects of hUCMSC should be thoroughly examined in future studies.</p>
</sec>
<sec sec-type="data-availability" id="s6">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.</p>
</sec>
<sec sec-type="author-contributions" id="s7">
<title>Author contributions</title>
<p>XW and TL conducted study collection, indentification, data extraction, and statistical disposal. XW drafted the manuscript. TL polished the manuscript. XB, YZ, and MZ collected the relevant references and participated in the discussion. LW designed this meta-analysis and revised the manuscript. All authors contributed to this manuscript. All authors read and approved the final manuscript.</p>
</sec>
</body>
<back>
<sec sec-type="funding-information" id="s8">
<title>Funding</title>
<p>This work was supported by Department of Science and Technology of Zhejiang Province, Lingyan Project (2022C03097).</p>
</sec>
<sec sec-type="COI-statement" id="conf1">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s9">
<title>Publisher&#x00027;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<fn-group>
<title>Abbreviations</title>
<fn fn-type="abbr"><p>AMH, anti-mullerian hormone; ART, assisted reproductive technology; CI, confidence interval; CVD, cardiovascular disease; E<sub>2</sub>, estradiol; FSH, follicle stimulating hormone; GC, granulosa cell; GSC, germline stem cell; GnRH, gonadotropin-releasing hormone; HRT, hormone replacement therapy; hUCMSC, human umbilical cord mesenchymal stem cell; IVA, <italic>in vitro</italic> activation; IVF-ET, <italic>in vitro</italic> fertilization and embryo transfer; LH, luteinizing hormone; MeSH, medical subject heading; POF, premature ovarian failure; POI, primary ovarian insufficiency; PRISMA, preferred reporting items for meta-analysis and systematic review; RCT, randomized clinical trail; RR, risk ratio; SMD, standardized mean difference; TC, theca cell.</p></fn></fn-group>
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